Journal of Medicinal Chemistry p. 7910 - 7922 (2019)
Update date:2022-08-02
Topics:
Janssen, Antonius P.A.
Van Hengst, Jacob M.A.
Béquignon, Olivier J.M.
Deng, Hui
Van Westen, Gerard J.P.
Van Der Stelt, Mario
Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis-Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase inhibitors is expected to aid in the discovery and development of more selective covalent inhibitors.
View MoreChemtn Biological Technology Limited
website:http://chemin.lookchem.com/
Contact:15532449001
Address:LB BLDG,Qiaoxi district,Shijiazhuang,china
website:http://www.finerchem.com
Contact:+86-531-88989536
Address:New Material Industry Park, Jinan Ciyt, China
Jinan Kaypharm Chemical Co.,Ltd
Contact:86-0531-86986780
Address:Room101,No189-2,Huayuan Road,Jinan City,Shandong Province
website:http://www.apeptides.com/en/
Contact:+86-21-60871011
Address:No. 80 Chuanshan Shuyuan Steet,Pudong,Shanghai
Triumph International Development Limilted
website:http://www.jiashengchem.cn/
Contact:+86-536-7971999
Address:Yinhai Road,Shouguang
Doi:10.1021/ja01600a042
(1956)Doi:10.1021/ja01628a095
(1955)Doi:10.1039/c39860000903
(1986)Doi:10.1080/00397911.2011.552834
(2012)Doi:10.1021/ja00794a015
(1973)Doi:10.1002/hlca.201200042
(2012)